Causes and consequences of β-thalassemia. (A) During the early stages of BT, as well as in the absence of transfusion or when transfusion is inadequate, IE and erythroid expansion are responsible for hepcidin suppression, likely through erythroferrone. (B) This leads to increased iron absorption and iron overload. (C) Over time, splenomegaly occurs, exacerbating extramedullary erythropoiesis, RBC sequestration, anemia, and hypoxia. In particular, hypoxia stabilizes a transcription factor called HIF2α in enterocytes (D), which increases expression of ferroportin, among other iron-related molecules, in the duodenum (E). Therefore, the relative balance of hepcidin vs ferroportin is such that iron absorption is still increased, despite the fact that iron overload is promoting hepcidin expression.